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Biomedical subjects

A Gringeri

Publications and source records attributed to A Gringeri.

At least 73 records · Page 4Linked to original sources
PubMed1994

Patients with severe von Willebrand disease are insensitive to the releasing effect of DDAVP: evidence that the DDAVP-induced increase in plasma factor VIII is not secondary to the increase in plasma von Willebrand factor.

It is generally held that factor VIII (FVIII) does not increase in the plasma of severe von Willebrand disease (vWD) patients treated with DDAVP because they lack von Willebrand factor (vWF), which is the plasma carrier for FVIII. To test this hypothesis, FVIII plasma levels were monitored in severe vWD patients treated with DDAVP after normalization of vWF plasma levels with infusions of cryoprecipitate. Each of four severe vWD patients underwent four different treatments at intervals of at least 15 d: (1) cryoprecipitate plus DDAVP; (2) cryoprecipitate plus saline; (3) cryoprecipitate plus recombinant FVIII (rFVIII); (4) saline plus rFVIII. Cryoprecipitate increased the plasma levels of FVIII and vWF. The infusions of saline or DDAVP after cryoprecipitate did not further increase FVIII and vWF plasma levels and had no effect on the plasma levels of tissue plasminogen activator (tPA), which are raised by DDAVP in normal subjects and in patients with vWD of other types. The infusion of rFVIII further increased by 182 +/- 32 U/dl (mean +/- SEM) the plasma levels attained after cryoprecipitate, which disappeared from the circulation with a half-life of 11.95 +/- 0.86 h. In contrast, the infusion of rFVIII after saline increased by only 107 +/- 18 U/dl the plasma levels of FVIII, which disappeared from the circulation with a half-life of 2.68 +/- 0.14 h, indicating that the vWF infused with cryoprecipitate is able to bind additional FVIII. These studies indicate that DDAVP does not increase the plasma levels of FVIII in patients with severe vWD even after normalization of plasma vWF. The possibility is discussed that severe vWD patients may be insensitive to the releasing effect of DDAVP.

Deamino Arginine Vasopressin↗
PubMed1994

Prevalence of infection with the hepatitis C virus among Italian hemophiliacs before and after the introduction of virally inactivated clotting factor concentrates: a retrospective evaluation.

In July 1985, all coagulation factor concentrates were withdrawn from the market in Italy and replaced with virally inactivated concentrates. A retrospective survey comparing the prevalence of the antibody to the hepatitis C virus (anti-HCV) in hemophiliacs multitransfused with nonvirally inactivated concentrates until 1985 with that in previously untreated hemophiliacs transfused exclusively with virally inactivated concentrates since 1985 has been conducted in 9 Italian hemophilia centers. The centers, which follow about one-fourth of all the Italian hemophiliacs, provided information about 708 patients infused for the first time before 1985 (group A) and 80 patients infused for the first time between 1985 and 1991 (group B). The prevalence of anti-HCV was 83% (591/708) in group A and 6% (5/80) in group B. For the 5 anti-HCV-seropositive patients from group B, dry heating, hydrophobic interaction chromatography plus dry heating (2 patients), hot vapor and pasteurization were the virucidal methods used for the concentrates implicated in HCV transmission. In the case associated with pasteurization, there is the possibility of intrafamilial transmission of HCV. It appears from this retrospective analysis that there has been a substantial reduction in the risk of HCV transmission since the adoption of virucidal methods. However, these methods do not eliminate completely the risk, which might be further reduced by the recent adoption of anti-HCV screening for plasma donations used to manufacture concentrates.

Blood Coagulation Factors↗
PubMed1994

The role of stem cell factor in mobilization of peripheral blood progenitor cells.

Stem cell factor (SCF) is a hematopoietic growth factor which acts on both primitive and mature progenitors cells. In animals, high doses of SCF alone stimulate increases in cells of multiple lineages and mobilize peripheral blood progenitor cells (PBPC). Phase I studies of rhSCF have demonstrated dose related side effects which are consistent with mast cell activation. Based upon in vitro synergy between SCF and G-CSF we have demonstrated the potential of low doses of SCF to synergize with G-CSF to give enhanced mobilization of PBPC. These PBPC have increased potential for both short and long term engraftment in lethally irradiated mice and lead to more rapid recovery of platelets. On going Phase I/II studies with rhSCF plus rhG-CSF for mobilization of PBPC, demonstrated similar increases in PBPC compared to rhG-CSF alone. These data suggest a clinical role of rhSCF in combination with rhG-CSF for optimal mobilization of PBPC.

Animals↗
PubMed1994

Virology of the hepatitis A epidemic in Italy.

We studied the virologic aspects of a hepatitis A epidemic that occurred among hemophilia patients in Italy between 1989 and 1992. Twelve lots of factor VIII concentrate manufactured by the solvent-detergent chromatographic technique and suspected of contamination by the hepatitis A virus (HAV) were analyzed by a two-step, nested polymerase chain reaction (PCR) procedure. PCR was applied to 1-ml samples of factor VIII concentrate and 100-microliters serial serum samples available from 2 patients. Particular care was taken to rule out the possibility of false-positive results during analysis. Results demonstrated PCR amplification of the 3'-region of the VP3 gene in 5 of the 12 implicated lots of factor VIII and in the serial serum samples of both patients. PCR amplification also revealed that the gene sequences detected in patients' sera were identical to the sequences detected in the product they had received. In all, 3 VP3 sequences (found to be 96-99% identical) were amplified. Further characterization of the HAV found in the factor VIII concentrate and the patients' sera was attempted by PCR amplification of the VP1/2A region. Successful amplification of this region was achieved in the serum of only 1 patient and in the concentrate he received. This fourth amplified sequence was identical in both serum and factor VIII concentrate. Attempts to transmit hepatitis A from the contaminated lots to 3 chimpanzees resulted in no signs of infection after 10 months of observation. Based on the Italian experience, persons with severe hemophilia who receive large-pool concentrate are at potential risk for HAV infection and should be vaccinated against HAV or use an alternative to solvent-detergent-prepared concentrate.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Patterns of immunogenicity of an inactivated hepatitis A vaccine in anti-HIV positive and negative hemophilic patients.

Hepatitis A vaccination has been recommended to patients with hemophilia since they are exposed to potentially infectious clotting factor concentrates. Aim of this study was to assess the immunogenicity of vaccination in hemophiliacs, infected or not with the human immunodeficiency virus (HIV). A formalin-inactivated hepatitis A vaccine was injected subcutaneously to 113 susceptible adults and children and repeated after 1 and 6 months. 47 vaccinees were anti-HIV positive (28 asymptomatic, 15 with CD4 cell counts of less than 200/microliter and 4 with symptomatic disease). The first dose of vaccine induced seroconversion, with antibody titers of at least 20 mIU/ml, in 89% of the 66 anti-HIV negative patients, 100% of them responding after the second injection. In anti-HIV positive hemophiliacs seroconversion rates and antibody titers were significantly lower than in non-infected patients. After 12 months, only 76% of anti-HIV positive vaccinees and 40% of those with signs of HIV disease progression maintained the antibody, whereas all anti-HIV negative patients had titers of 20 mIU/ml or more. Our results indicate that there is an association between defective response to hepatitis A vaccine and stage of progression of HIV disease.

Adolescent↗
PubMed1994

A randomized, placebo-controlled, blind anti-AIDS clinical trial: safety and immunogenicity of a specific anti-IFN alpha immunization.

HIV-induced cytokine dysregulation, including overproduction of the antiproliferative and cytolytic IFN alpha cytokine, represents a major component of the immune disorders characterizing AIDS. To block the overproduction of IFN alpha we designed an AIDS vaccine combination which included both an anti-HIV and/or an anti-IFN alpha immunization. The safety and immunogenicity of this multicomponent vaccine were tested in mice, Cercopithecus, two HIV noninfected individuals, and six HIV-1 seropositive immunocompromised patients enrolled in a 1-year open clinical trial. We now report the result of a 9-month short-term randomized, blind, placebo-controlled clinical trial (Phase I/II) performed in HIV-1 patients (22 individuals) to confirm safety/tolerance of the anti-IFN alpha vaccine and its immunogenicity and to evaluate whether the complex vaccine initially used could be simplified by removal of HIV component(s). Three groups of patients received inactivated IFN alpha (i-IFN alpha) associated with the immunomodulator P40 with HIV-1 antigens (groups B and C) or without (group A), and one group (D) was placebo. The clinical follow-up documented among those receiving i-IFN-alpha showed that none developed AIDS and/or required antiretroviral chemotherapy. Viral load did not increase and CD4 cell count as well as cell-mediated immunity (CMI) stabilized or even significantly increased in group A. Immunogenicity of the preparations was determined by a positive delayed-type hypersensitivity (DTH) reaction to i-IFN alpha and the presence of serum antibodies to i-IFN alpha and to HIV-1 peptides, occurring only in treated patients. As previously planned, based on these safety data, the trial has been extended for an additional year and all patients were switched to protocol A (i-IFN alpha+P40). This second period of the trial, now open and ongoing, should allow us to evaluate further the innocuity of the i-IFN alpha preparation and whether anti-IFN alpha vaccine could provide a long-lasting CD4 cell count as well as CMI stabilization.

AIDS Vaccines↗
PubMed1994

Markers of hypercoagulability in patients with hemophilia B given repeated, large doses of factor IX concentrates during and after surgery.

Purer factor IX (FIX) concentrates have been produced for the treatment of hemophilia B in the attempt to reduce the risk of thrombotic complications associated with the use of prothrombin complex concentrates. To evaluate ex vivo whether or not FIX concentrates activate the coagulation system in conditions associated with a high risk for thrombosis, we measured markers of hypercoagulability in 10 patients with hemophilia B who underwent surgery, mainly orthopedic procedures, covered by multiple concentrate infusions (40-80 U/kg/day). Postinfusion plasma levels of prothrombin fragment 1 + 2 and factor X activation peptide did not differ significantly from the presurgical levels, neither before nor after each concentrate dose. Therefore, it appears that prolonged treatment of patients with hemophilia B undergoing high risk surgical procedures with high doses of FIX concentrate does not cause systemic activation of coagulation. This suggests that purified FIX concentrates are preferable to prothrombin complex concentrates for conditions associated with an increased risk of thrombosis.

Adolescent↗
PubMed1993

Accelerated schedule of hepatitis B vaccination in patients with hemophilia.

Early development of immunity after hepatitis B vaccination is particularly important for patients such as hemophiliacs, at high risk for acquiring hepatitis B from potentially infectious plasma-derived concentrates. The purpose of this study was to evaluate whether or not protective antibody titers could be achieved quickly and maintained in hemophiliacs by an accelerated vaccination schedule. A yeast-recombinant hepatitis B vaccine (Engerix B, SKF Ritt) was given subcutaneously in the deltoid region and repeated 2 and 6 weeks later to 85 hemophiliacs negative for hepatitis B virus (HBV) markers. After the first 22 patients had been enrolled, a modification of the schedule involving a fourth booster dose 24 weeks after the first dose of vaccine was applied to the next 63 consecutive vaccines. Fifty-three percent of vaccinees had antibody titers to hepatitis B surface antigen (anti-HBs > or = 10 mlU/ml) by week 6, even though the mean titers of anti-HBs were somewhat lower than those achieved historically in normal individuals. The protection rate had increased to 87% by week 10, one month after the third dose of vaccine, and to 93% by week 24. One year after starting vaccination, the rate for the vaccinees who did not receive the fourth booster dose was 71%, and 96% for those who did receive the fourth dose, with only 2 patients not responding despite the booster dose. It is concluded that even though the accelerated schedule of immunization produced rapidly high rates of protective antibody titers, a booster dose is required to obtain higher titers and provide more persistent immunity.

Adolescent↗
PubMed1993

Long-term treatment with zidovudine in patients with human immunodeficiency virus (HIV)-associated thrombocytopenia: modes of response and correlation with markers of HIV replication.

The effects of zidovudine on the platelet count were studied in 152 patients with HIV-related thrombocytopenia of severe grade (platelet count < 50 x 10(9)/l) and moderate grade (platelet count < 100 and > 50 x 10(9)/l). In both groups of patients there was a significant increase in the mean platelet count from the baseline value, after 2 weeks (from 21 x 10(9)/l to 48 x 10(9)/l and from 75 x 10(9)/l to 97 x 10(9)/l) and 3 months of therapy (to 59 x 10(9)/l and to 144 x 10(9)/l). Sixty-five and 39 patients were followed up for 12 and 18 months, respectively, and the mean platelet values after 12 and 18 months of therapy were still significantly increased, compared to the respective mean baseline values, in both groups of patients. Clinical progression of the disease was observed in 23 treated patients, none of them showing concomitant reductions of the platelet number. An increase in the mean CD4+ cell count after 3 months of therapy was followed by a progressive decline in the 65 patients with a 12-month follow-up, while no significant changes of the p24 antigenemia rates were observed after 1 year of therapy in 53 patients evaluated. The long-term effects of zidovudine on the platelet count, but not on other parameters of clinical outcome, might be explained by the involvement of specific mechanisms in the pathogenesis of this kind of thrombocytopenia and of its response to zidovudine.

Acquired Immunodeficiency Syndrome↗
PubMed1992

The low risk of hepatitis C virus transmission among sexual partners of hepatitis C-infected hemophilic males: an international, multicenter study.

To study the transmission rate of hepatitis C virus (HCV) in the female sexual partners of antibody-positive hemophilic males, 106 partners from three hemophilia centers located in Europe, America, and Australia were tested for HCV seropositivity using a first-generation enzyme-linked immunosorbent assay (ELISA-1) and, subsequently, a second-generation ELISA (ELISA-2) and a supplemental recombinant immunoblot assay. Additionally, the cohort was tested for the presence of antibody to the human immunodeficiency virus type-1 and hepatitis B virus markers. No female partner was HCV antibody-positive using the ELISA-1 test, whereas five were seropositive by the ELISA-2 test. Three of these five female partners were seropositive on the supplemental test, the remaining two having indeterminate results, for an overall prevalence of 2.7%. Thus, even with the use of sensitive testing, the prevalence of HCV infection remains low in this cohort, showing that the efficiency of heterosexual transmission of HCV is poor.

Enzyme-Linked Immunosorbent Assay↗
PubMed1992

Factor IXa-factor VIIIa-cell surface complex does not contribute to the basal activation of the coagulation mechanism in vivo.

We have infused recombinant factor VIIa into patients with hereditary factor VII deficiency with marked reductions in plasma concentrations of factor IX activation peptide (FIXP), factor X activation peptide (FXP), and prothrombin activation fragment F1+2. These investigations show substantial elevations in these markers of coagulation activation and thereby demonstrate that the factor VII-tissue factor pathway is largely responsible for the activation of factor IX as well as factor X in the basal state (ie, the absence of thrombosis or provocative stimuli). We have administered a monoclonal antibody purified factor IX concentrate to individuals with hemophilia B. These studies show an increase in the plasma levels of FIXP that were initially greatly decreased, but no change in FXP or F1+2. We have also infused highly purified factor VIII concentrate into patients with hemophilia A. The data demonstrate no significant changes in the plasma concentrations of FXP and F1+2. The above observations indicate that factor IXa generated by the factor VII-tissue factor pathway is unable to activate factor X under basal conditions. Based upon the above findings, we outline a model of blood coagulation system function under basal conditions, and suggest a process by which the generation of factor Xa and thrombin might be accelerated during normal hemostasis and in the setting of thrombotic disorders.

Adolescent↗
PubMed1992

Immune status of asymptomatic HIV-infected hemophiliacs: randomized, prospective, two-year comparison of treatment with a high-purity or an intermediate-purity factor VIII concentrate.

It has been postulated that high-purity factor VIII (FVIII) concentrates, since they contain less alloantigenic proteins than intermediate-purity concentrates, might cause lesser deterioration of the immune systems of hemophilic patients infected with the human immunodeficiency virus (HIV). To evaluate this hypothesis, we have prospectively compared T-lymphocytes subsets and delayed hypersensitivity reactions to skin tests in 17 asymptomatic HIV-positive hemophiliacs randomly assigned to continue treatment with an intermediate-purity concentrate with those of 16 hemophiliacs changed to a high-purity concentrate. For both groups, during the 24-month follow-up period CD4 cell counts showed similar rates of fall from baseline values. There was also no difference in the number of patients anergic to skin tests. Three patients treated with the intermediate purity concentrate and one treated with the high-purity concentrate developed symptoms of HIV infection. On the whole, no striking benefit is conferred to the immune status of asymptomatic HIV-positive hemophiliacs by using this high-purity concentrate for 2 years.

Adolescent↗
PubMed1992

Low risk of transmission of the human immunodeficiency virus by a solvent-detergent-treated commercial factor VIII concentrate.

A study evaluating the risk of a commercial factor VIII (FVIII) concentrate's transmitting the human immunodeficiency virus (HIV) was carried out on hemophiliacs, by using multiple serological markers and the polymerase chain reaction (PCR). Twenty-nine hemophiliacs, negative for HIV antibodies, were treated for 18 months with a concentrate that had been inactivated by solvent-detergent. HIV-1 antibodies and antigen were assayed during the follow-up period. At the end of the study, all patients were also tested by the HIV 1 + 2 combined antibody assay; Western blot (WB) antibody analysis; and in eight cases, by an HIV-1 PCR technique. Patients received a yearly median FVIII dose of 35,330 IU (range 3,300-306,000); the median number of lots given to each patient was 6 (1-45). During the follow-up period and at the end of the study, HIV-1 antibodies and antigen were not detected in any of the subjects. The HIV 1 + 2 combined assay and WB analysis carried out only at the end of the study were negative. HIV-1 PCR was negative in all the tested patients. This study has shown that this solvent-detergent-treated FVIII concentrate did not transmit HIV.

Detergents↗
PubMed1992

PCR analysis of HIV-1 sequences and differential immunological features in seronegative and seropositive haemophiliacs.

We have compared the immunological features of two matched groups of seronegative and seropositive haemophilia A individuals. Both groups were exposed from 1981 to 1985 to comparable amounts and batches of FVIII concentrates not subjected to virus inactivation procedures, and had therefore a 100% probability of receiving HIV-contaminated material. The presence of proviral HIV-1 sequences was evaluated by PCR in the DNA from peripheral blood lymphocytes and/or monocytes. After hybridization with specific probes, DNA from all seropositive haemophiliacs revealed HIV sequences; no HIV sequences were observed from the DNA of seronegative patients, even after two rounds of amplification, thus suggesting that these patients were not affected by a latent HIV infection. Seronegative/PCR- and seropositive/PCR+ patients showed a normal and reduced number of CD4+ lymphocytes, and a slight and marked increase of CD8+ cells respectively. Activated T cells expressing the HLA-DR antigen were elevated in both groups. Interestingly, a significant reduction of circulating CD56+/CD3- NK lymphocytes was observed only in seropositive haemophiliacs, whereas NK lymphocytes with CD56+/CD3+ phenotype were within normal levels in both groups. In seropositive patients no correlation was found between the number of CD4+ and CD56+/CD3- lymphocytes. The marked reduction of CD56+/CD3- lymphocytes observed in seropositive haemophiliacs in addition to the CD4+ cell depletion may represent a key pathogenetic factor which facilitates the onset and/or the progression of HIV-1 infection in haemophiliacs, and is related to the capacity of HIV to infect NK cells.

Antigens, CD↗
PubMed1992

Intramuscular anti-D immunoglobulins for home treatment of chronic immune thrombocytopenic purpura.

To assess the efficacy of home treatment with intramuscular anti-D immunoglobulins (anti-D IgG) in patients with idiopathic or HIV-related chronic immune thrombocytopenic purpura (ITP), we conducted an open label, non-controlled, prospective study with a follow-up of 6 months in 51 consecutive patients with HIV-related (n = 24) or idiopathic ITP (n = 27). Anti-D IgG (13 micrograms/kg) were infused intravenously for three consecutive days (induction therapy). Patients whose platelet counts failed to increase above 50 x 10(9)/l were given a second course of the same therapy. If their platelet counts remained lower than 50 x 10(9)/l, they were considered non-responsive. Patients who responded to induction therapy were injected intramuscularly with 6 micrograms/kg/week anti-D IgG if platelets were between 50 and 100 x 10(9)/l or 13 micrograms/kg/week if they dropped to less than 50 x 10(9)/l. After induction therapy, responses occurred in 20/24 HIV-related chronic ITP patients (83%) and in 14/27 idiopathic chronic ITP patients (52%). During follow-up, platelets remained above 50 x 10(9)/l in 17/20 HIV-related chronic ITP patients (85%) and in 8/14 (57%) idiopathic chronic ITP patients. We conclude that anti-D IgG are a valid therapeutic option for treatment of idiopathic and HIV-related chronic ITP, since they are safe, cheap and can be given intramuscularly at home.

Adolescent↗
PubMed1991

Adverse effects of treatment with porcine factor VIII.

In the last 10 years 63 courses (283 infusions) of porcine FVIII were given to 25 hemophiliacs with high titer alloantibodies and to 5 patients with autoantibodies to factor VIII. Although the product was in general clinically efficacious, adverse effects of treatment were more frequent and severe than previously reported. After 63 courses there was a median percentage fall in baseline platelet count of 54% (range 8-86%); for 10 courses (16%), thrombocytopenia was severe or moderately severe (less than 100 x 10(9)/l), with nadirs of platelet count ranging from 10 to 99 x 10(9)/l (median 67). Allergic reactions were seen in 15 of 30 patients (50%), in 20 of 63 courses (32%), more frequently but not exclusively after the first infusion. Relatively mild symptoms (fever, flushing, urticaria, shivering) occurred in 15 courses; 5 courses, however, were accompanied by more severe anaphylactoid reactions, 2 of which required resuscitation therapy. Allergic reactions were observed both in patients pretreated with steroids or anti-histamines (in 7 of 18 courses, 39%) and in nonpretreated patients (in 13 of 45 courses, 29%). In conclusion, adverse reactions are frequent after porcine FVIII (in 30 of 63 courses, 47%), and can occur also with infusions subsequent to the first. Hence, the recently proposed use of porcine FVIII as home treatment should be implemented with caution.

Adolescent↗
PubMed1991

Progression to AIDS among Italian HIV-seropositive haemophiliacs. Italian Group.

To investigate the interval between HIV-1 infection and the development of clinical AIDS among Italian patients with congenital coagulation disorders, a national cohort study was undertaken in 1988. Information was collected both retrospectively and prospectively on 499 HIV-1-positive patients enrolled in an ongoing national registry of patients with congenital coagulation disorders. Two methods were used to estimate each patient's seroconversion date: the mid-point between the last negative (either known or estimated) and the first positive test, and the median under a Weibull distribution, which was assumed to fit seroconversion data. The two methods of estimating the seroconversion time yielded similar results. The actuarial incidence of AIDS was estimated using the Kaplan-Meier survival analysis at 12.8% (95% confidence interval = 9.7-15.9) over 7 years for Italian haemophiliacs. Progression appears to be slow in the first 5 years after the infection, and to rise steadily thereafter. A strong association between faster progression and older age at seroconversion was found. Zidovudine-treated individuals seem to have a slower progression than untreated individuals, after controlling for CD4, but there was no association between progression and type and severity of the congenital disorder.

Acquired Immunodeficiency Syndrome↗